Process and apparatus for the agglomeration of hydrolytically sensitive substances by means of steam

ABSTRACT

In the process for the agglomeration of slightly soluble and hydrolytically sensitive substances, a powder of the slightly soluble substance is conducted, together with at least one water-soluble binder, in free fall through a steam atmosphere at temperatures between 85° C. and 105° C. essentially without the action of compacting forces. In this process, the residence time in the steam atmosphere is approximately 0.5 to 10 seconds. The agglomerates formed are then dried in free fall, so that small solid bridges form from the binder liquid bridges formed at the points of contact between the primary particles. In a following integrated fluidized-bed dryer, the final drying then takes place to a water content of less than 0.5% by weight. The process is carried out in a steam jet agglomerator in which a freely falling product curtain of the pulverulent mixture to be agglomerated is impinged by steam using steam jet nozzles (5, 6). A fluidized-bed dryer (2) is connected at the lower part of the agglomerator (1) in such a manner that the agglomerated particles (4) fall directly into the fluidized bed.

The invention relates to a special process for the agglomeration ofslightly soluble and hydrolytically sensitive substances, in particularpharmaceutical active substances, such as acetylsalicylic acid (ASA), byusing steam. In addition, the invention relates to an apparatus forcarrying out the process.

Many substances in powder form are difficult to disperse in liquids, andtherefore their use for dispersions or solutions is often troublesome.Frequently, moreover, good flow behavior and a very low dust content aredesired. This also applies to slightly soluble powders which can haveboth hydrophilic and hydrophobic surface properties. If powders are usedfor pharmaceutical preparations, it is, furthermore, frequentlydesirable or necessary to improve or mask tastes or to avoid or minimisecontact with other incompatible mixing components.

The improvement in the wetting, flowability and the reduction of thedust content in the use of powders is customarily achieved bygranulating the relevant powders by a process of agglomeration.Agglomeration processes are characterized by the use of granulatingliquids, customarily water or aqueous solutions. These processes aretherefore not applicable to processing hydrolytically sensitivesubstances, since in this case, generally, the (active) substancedecomposes, with the formation of (pharmaceutically) undesirabledegradation products. If, therefore, non-aqueous organic solvents areused, this leads to solvent residues in the granules which are likewiseundesirable or impermissible. Furthermore, working with a solventincreases the expenditure on processing.

It has been found that readily dispersible granules are obtained if theagglomeration process produces, between the primary particles, verysmall solid bridges which can be easily broken up on redispersion in aliquid and preferably comprise a material which is freely soluble in theliquid. It is further advantageous here for the ready dispersibility ofthe granules if, during the agglomeration, i.e. in the still moist stateof the granules, compacting forces are avoided, since otherwise thepoints of contact between the moistened particles are enlarged andrelatively large relatively stable solid bridges are formed.

The invention relates to a process for the agglomeration ofhydrolytically sensitive substances, in particular ASA, characterized inthat the slightly soluble ASA powder is conducted together with at leastone freely water-soluble pulverulent binder in free fall through a steamatmosphere at temperatures between 85° C. and 105° C., preferably atapproximately 100° C., essentially without the use of compacting forces,with a residence time in the steam zone of approximately 0.5 to 10seconds, preferably 1 to 3 seconds, and is then initially dried infurther free fall so that, at the points of contact between theparticles of the water-insoluble active substance and the water-solublebinder, small solid bridges are formed from the liquid bridges which areformed owing to the condensation and in which binder is dissolved, andin a subsequent drying operation in an integrated fluidized bed is driedto a water content of less than 5% by weight, preferably less than 1% byweight.

"Small solid bridges" is taken to mean that the solid bridges shouldhave a mean transverse dimension (diameter or thickness) of 1 μm to 30μm, preferably 5 to 15 μm.

As a result of the fact that the contact time of the water with thehydrolytically sensitive powder is very short, and also the heat stressof the solid particles at a maximum of 100° C., preferably at a maximumof 86° C., is low and is present only very briefly, no significantdegradation reactions occur during the process according to theinvention.

The partial solution of the particle surface of the binder by thecondensed steam proceeds very rapidly, the resulting solutions formliquid bridges at the contact points between the particles or are drawnon to the slightly soluble hydrolytically sensitive particles. Theimmediate evaporation of the water occurring after the agglomerationwith the formation of solid bridges (or partial) encasing of theinsoluble active substance particles by the water-soluble auxiliariesensures stability even in the case of hydrolytically sensitivesubstances, such as ASA.

Using the method described, if suitable ratios of active substance andauxiliary and expedient process conditions are selected, a type ofmicroencapsulation or coating of the water-insoluble substances is alsopossible.

For the agglomeration or partial) microencapsulation of the slightlysoluble or insoluble substances, freely water-soluble bindingauxiliaries are used, such as polyvinylpyrrolidone (PVP), PVPderivatives, starch, starch and cellulose derivatives, sugars, sugaralcohols such as sorbitol, xylitol, sugar derivatives such asmaltodextrin, isomaltose, fruit acids and their water-soluble salts,such as citrates or tartrates, ascorbic acid, amino acids or inorganicsalts such as sodium sulphate.

The weight ratio of the slightly soluble active substances to thewater-soluble binding auxiliaries is 1 to 10 to 10 to 1, preferably 3 to8 to 7 to 2. The mixture to be agglomerated of hydrolytically sensitiveinsoluble active substance and water-soluble auxiliary is advantageouslyintroduced into the apparatus from the top, together with the steam inspatial proximity. The steam condenses on the colder powder particles,the condensate film partially dissolves the binder, and the liquidbridges formed at the contact points between the moistened particles aredried to form solid bridges. In the case of a great excess ofwater-soluble auxiliaries, the hydrolytically sensitive active substancecan be completely shielded by the water-soluble auxiliary. The processcan also be employed in such a manner that a freely water-soluble activesubstance acts as binder.

An essential element of the process according to the invention is theuse of a virtually pure steam atmosphere for the direct moistening ofthe particle surface. If air were simultaneously present, air cushionsto the particle surface would otherwise have to be crossed by the steamby diffusion. As a result, less steam can condense on the solid, andthere is thus a lower degree of agglomeration or shielding of the activesubstance. Thus, the aim of treating the hydrolytically sensitive powdercannot be achieved, or is achieved to only an unsatisfactory extent.

To carry out the process according to the invention, an apparatus hasproved useful which comprises an agglomerator having a closed housing,at the upper end of which a metering apparatus for a pulverulentmaterial connected to a feed hopper is mounted by which a freely fallingproduct curtain of pulverulent material in the agglomerator is produced.In addition, the apparatus is equipped in the upper part of theagglomerator with nozzles for producing steam jets which at leastpartially surround the freely falling product curtain within a steamzone. The characteristic according to the invention of this apparatus isthat at the lower part of the agglomerator, a fluidized-bed dryer isconnected in such a manner that the agglomerated particles fall directlyinto the fluidized bed. The fluidized-bed dryer is thus directlyintegrated into the steam jet agglomeration apparatus.

Advantageously, the steam jet nozzles consist of tubes or bore holeswhich are connected to a distributor tube extending in the longitudinaldirection of the agglomerator, one distributor tube being arranged ateach of the two sides of the product curtain.

An essential element of the apparatus according to the invention is alsothe separation of the steam zone (moistening zone) from the drying zone.This separation is achieved according to a further development of theinvention by means of the fact that a heated double-walled protectivetube which encloses the steam jet nozzles in the upper part of theagglomerator is arranged and through the jacket of which protective tubeexhaust air is taken off. In this manner, all of the gas streamsintroduced into the apparatus by the fluidized-bed dryer can be takenoff at the lower end of this protective tube.

Alternatively, the steam zone can also be separated from the drying zoneby means of the fact that a ring gap having a collection channel to takeoff the exhaust air is provided on the agglomerator housing at adistance of 50 mm to 300 mm from the lower end of the steam jet nozzledistributor tubes. In this manner, likewise, all of the exhaust air canbe taken off evenly over the entire periphery of the apparatus in theregion between the evaporation and drying sections.

A preferred development of the apparatus according to the invention isthat the fluidized-bed dryer integrated into the steam jet agglomeratorhas an annular conically ascending outer fluidizing plate and a centralinner fluidizing plate, the flow velocity of the fluidizing air exitingat the inner plate being greater than the flow velocity of thefluidizing air at the outer plate.

Advantageously, connected to the conical outer fluidizing plate is alikewise conical widening of the agglomerator housing. These measurescause a circulating motion of the bed and prevent an undesirable localovermoistening. The desired final moisture can be set by an appropriateresidence time in the drying zone and/or appropriate choice of thedrying air rate and drying air temperature in the fluidized bed. Thetemperature in the fluidized bed in this case is between 20° C. and 70°C.

By means of the invention, the following advantages are achieved:

On account of the low agglomeration moistures, temperature stress and,especially, the very short stress duration, even hydrolyticallysensitive products may be successfully processed by moistureagglomeration by means of the process. Even in the case of sensitiveproducts, no, or only minimal, degradation reactions occur.

Agglomerates in the size range between 200 and 3000 μm, preferablybetween 200 and 2000 μm, can be produced by the process according to theinvention.

The agglomerates produced by the process are extremely highlyredispersible. Even for redispersion in cold water, only very shorttimes are required (usually less than 1 minute, preferably <30 seconds),which can be achieved for granules which are produced by customarilyemployed agglomeration processes (mixer agglomeration, fluidized-bedagglomeration) only with redispersion in hot water.

For bad-tasting products, good taste masking is achieved in theprocessing with good-tasting products and/or flavorings.

If appropriate process conditions are selected (in particular if asufficiently high binder content is selected), it is possible not onlyto agglomerate insoluble products but also partially to enclose them. Inthis case, the surface of the insoluble particles is coated with thedissolved binder, if the binder solutions are spreadable on theinsoluble product. In this case, a surface coverage of 40 to 80%,preferably 50 to 70%, can be achieved. This has the advantage that theproducts thus enclosed have a reduced reactivity to other mixingconstituents. Thus, mixtures of substances can also be produced whichusually have only a decreased storage stability.

The very good agglomerate solubility is due to the fact that the bridgesbetween the (insoluble) particles to be agglomerated comprise a veryfreely soluble material (binder dissolves in fractions of a second inthe condensed steam), which is also very well wetted by water. Thebridges between the particles are, furthermore, only a few μm thick (1to 30 μm, preferably 5 to 15 μm) and concentrate at the points ofcontact between the particles. A high surface area is thus offered for adissolution process.

The invention is described in more detail below with reference toworking examples and drawings. In the drawings:

FIG. 1 diagrammatically shows the steam jet agglomeration apparatushaving an integrated fluidized-bed dryer

FIG. 2 shows a plan view of the steam jet nozzles equipped with thedistributor tubes

FIG. 3 shows the protective tube for the functional separation ofmoistening and drying of the descending product curtain

FIG. 4 shows an enlargement of the integrated fluidized-bed dryer.

According to FIG. 1, the steam jet agglomerator 1 and the fluidized-beddryer 2 are arranged vertically one above the other and are enclosed bythe same housing 3. The agglomerated product 4 leaving the steam jetagglomerator 1 falls directly into the fluidized-bed dryer 2. The steamis fed via two steam jet nozzles 5 and 6 which are connected in paralleland arranged on both sides of the descending product curtain. These aresupplied by a shared steam line 7. The steam jet nozzles 5, 6 are,furthermore, pivotable about the angle a. As shown in FIG. 2, the steamjet nozzles 5, 6 each consist of a multiplicity of short tubes 8 or boreholes which are connected to a distributor tube 9 extending in thelongitudinal direction of the agglomerator. The cross-section of thedistributor tubes 9 decreases over their length in such a manner thatthe nozzle tubes 8 are impinged by the same steam flow rate. The lengthof the nozzle tubes 8 is at least three times their diameter. Thedistributor tubes 9 and thus also the nozzle tubes 8 are pivotable aboutthe point of rotation 10, so that the angle at which the steam impactsthe product curtain is adjustable. The product curtain trickling pastthe steam nozzles 5, 6 is impinged by the steam within a steam actionpath d, whose length is essentially determined by the exit velocity ofthe steam and the pivot angle α. This steam action path is termed "steamzone" below. The angle α is adjustable between 0° and 6°. Optimum valuesare between 20° and 40°.

The solids are fed via a metering screw 11 into a longitudinal hopper12, at the lower end of which a uniform pulverulent product curtainexits through a slot and passes into the agglomeration section 1. Theparticles are thus brought into proximity with one another, but nocompacting forces occur. The region above the solids feed is likewisecovered by a separate cover 13, so that penetration of infiltrated airinto the apparatus is avoided, or only a controllable amount of airpasses into the apparatus via the product feed. Excessive infiltratedair would lead to a disruption of the steam atmosphere and to impairmentof the agglomeration action.

The product to be agglomerated and the binder are fed as a mixture tothe metering screw 11. The product in the reservoir can be heated orcooled by means of a heating or cooling medium, e.g. by conditioned air.The product temperature, i.e. the temperature of the powder mixture inthe metering screw, is a settable process parameter, which influencesthe amount of steam which condenses and thus directly influences theagglomeration result (agglomerate size, agglomerate moisture).

An important precondition to achieve reproducible process conditions andthus uniform product qualities is the spatial separation of thesteam-treatment zone and drying zone, so that on steam-treatment, avirtually pure steam atmosphere is ensured. For this purpose, a ring gap14 is provided on the housing 1 at the height of the point at which thesteam zone ends and the drying zone begins, which ring gap is connectedto a collection line 15. All of the exhaust air originating from thefluidized-bed dryer 2 is taken off through this ring gap. In practice,the ring gap 14 is at a distance of 50 mm to 300 mm below the lower edgeof the distributor tubes 9.

An alternative possibility for spatially separating the steam-treatmentzone and drying zone is plated on a protective cylinder (see FIG. 3)surrounding the steam zone. The protective cylinder 16 arranged on thecover 13 concentrically to the housing 1 is constructed with doublewalls. Hot air is injected into this jacket from below through acircular slot 17 in a ring tube 18 in order to heat the protectivecylinder 16 and to prevent steam from condensing on its walls.Furthermore, the ring tube 18 is mounted on the protective cylinder 16in such a manner that a ring gap 19 remains between the jacket and thering tube 18. Owing to the injector action of the injected hot pumpingair, air from the interior is drawn in (arrows 20) through this orificeat the lower rim of the jacket, so that a uniform take-off of theexhaust air from the dryer is ensured over the entire periphery. The hotpumping air is fed to the ring tube 18 through the pumping air branch21. The exhaust air is taken off from the jacket through the exhaust airbranch 22.

In the steam zone, the product curtain is moistened by condensation andas a result the agglomeration is induced. After the moistening, theagglomerated moist product first falls through a countercurrent streamof conditioned drying air originating from the fluidized-bed dryer andis pre-dried as a result. The subsequent drying to the desired finalmoisture is performed in an integrated fluidized bed. The desiredresidual moisture is achieved by means of the height of the fluidizedbed and by the choice of appropriate drying conditions (air temperature,air flow rate). The contents of the fluidized bed are kept constant at adesired value using a conventional level controller. The final moistureof the product can thus be set exactly, independently of the agglomeratemoisture achieved in the steam zone. The desired residual moisture is,in each case, not set until the formation of the solid bridges iscompleted. The granule size and granule structure depend on theformulation and the selected operating data (ratio of solids rate tosteam flow rate, solids temperature, drying conditions). Recirculatingsolids circuits, which can lead to separations, are not necessary.

According to FIG. 4, the fluidized bed in the dryer 2 is divided intovarious regions of differing fluidization intensity (flow arrows 23 and24). In the centre, the bed is fluidized more intensively, by means of aseparate central tube 25 having a perforated plate 26, than in theperipheral region in which the fluidization is carried out in a knownmanner by a conical perforated plate 27 ascending towards the outside.By this means, any still-moist product occurring is immediately mixedwith previously dried product and thus prevented from furthergranulation or clumping (sticking of the previously agglomeratedparticles to one another). This avoids the moist agglomerates whichimpact the fluidized bed from further agglomerating, sticking togetherand leading to the collapse of the fluidized bed. Between the perforatedplate 26 and the central tube 25 is arranged an annular discharge gap 28through which the dried end product is removed in accordance with thecontents of the fluidized bed, i.e. in accordance with its meanresidence time in the apparatus. This also ensures that no product canleave the apparatus directly, i.e. without prior circulation through thefluidized bed. Directly above the perforated plate 27, the apparatuswidens. This likewise conical widening 29 (towards the housing 1)reinforces the uniform circulation movement of the product and thus thedistribution of the still-moist impacting agglomerate and promotes themovement of particularly coarse particles towards the discharge 28. Bymeans of the combined measures of the specific varied fluidization andthe widening of the apparatus, a particularly uniform productcirculation is ensured.

The steam jet agglomeration apparatus according to the invention havingan integrated fluidized bed is operated with the following processparameters and product characteristics:

    ______________________________________    Flow rates    Steam            5 to 10 kg/h    Solids           10 to 100 kg/h    Residence times    Steam zone       0.5 to 3 s (preferably 0.5 to 1.5 s)    Fluidized bed    10 to 20 min    Temperatures    Steam            100° C.    Fluidizing air   20 to 80° C.    Bed temperature  20 to 50° C.    Product          0 to 60° C.    Product characteristics    Particle size    <300 μm (preferably <200 μm)    Binder content   5 to 90%    Agglomerate    Maximum moisture (downstream                     approx. 4 to 5%    of the steam zone)    Final moisture (downstream of the                     <0.5%    fluidized-bed drying)    Agglomerate size 200 to 2000 μm    ______________________________________

WORKING EXAMPLES Example 1

100 g of ASA powder are mixed with 50 g of xylitol as binder. Themixture, which is at room temperature, is introduced by means of thescrew 11 into the agglomeration apparatus in such a manner that a longuniform product curtain is formed. The solids mass flow rate is 20 kg/h.It is sprayed with 7 kg/h saturated steam at an angle α=30°. Theresidence time in the steam zone and thus the contact time with thesteam is 1 s. This forms granules in the size range preferably between150 and 1000 μm. The granules, directly after leaving thesteam-treatment zone, have moistures between 1.5% and 3% (determinedusing the Karl-Fischer titration method). The granules are then dried toresidual moistures below 1% in the downstream fluidized bed at bedtemperatures of 40° C. The residence time in the fluidized bed isbetween 10 and 20 min. The ASA/xylitol granules thus produced arereadily flowable, have a good taste and are outstandingly redispersible.The content of undesirable degradation products is below 0.5%.

Example 2

100 g of ASA powder are mixed with 200 g of xylitol as binder. Themixture, present at room temperature, is introduced by means of thescrew 11 into the agglomeration apparatus in such a manner that a longuniform product curtain is formed. The product mass flow rate is 30kg/h. It is sprayed with 10 kg/h of steam (saturated) at an angle α=40°.This forms granules in the size range preferably between 150 and 1000μm. The granules, directly after leaving the steam-treatment zone, havemoistures between 2.5 and 4% (according to Karl-Fischer titration). Thegranules are dried to residual moistures below 1% in the downstreamfluidized bed. The ASA/xylitol granules thus produced are readilyflowable, have a good taste and are outstandingly redispersible. Thecontent of undesirable degradation products lies below 0.5%. The surfaceof the ASA particles is 50 to 70% covered with xylitol. It is thuspossible to mix and store the ASA together with other components withwhich a joint mixture has not been possible hitherto, e.g. witheffervescent constituents or other basic components.

Example 3

100 g of ASA powder are mixed with 30 g of sucrose and 5 g of flavoring,preheated to 50° C. and introduced by means of the screw 11 into theagglomeration apparatus in such a manner that a long uniform productcurtain is formed. The product mass flow rate is 20 kg/h. It is sprayedwith 6 kg/h of steam at an angle α of 30°. Granules in the size rangebetween 200 and 1400 μm are preferentially formed. The granules,directly after leaving the steam-treatment zone, have moistures between1 and 2.5% (according to Karl-Fischer titration). The granules are driedto residual moistures below 0.5% in the downstream fluidized bed. Thegranules thus produced are readily flowable, have a good taste and areoutstandingly redispersible. The content of undesirable degradationproducts of ASA is below 0.5%, the loss of customarily volatile aromasubstances is below 10%. In this manner, it is possible to agglomerateASA together with flavorings. This offers the advantage that, incontrast to the conventional procedure, mixing flavorings only for thispurpose, separation in the course of further processing, transport andstorage up until use is prevented.

Example 4

100 g of ASA are mixed with 50 g of sodium sulphate and agglomerated bysteam jet as described in Example 1. After gentle drying, a readilyflowable agglomerate which can be very rapidly dispersed in water isobtained with this formulation also, which agglomerate can be employedfor sachet or tablet formulations.

Example 5

500 g of paracetamol are mixed together with 100 g of citric acid, 400 gof orange flavoring, 1000 g of lemon flavoring and 2000 g of maltitol asbinder. The mixture is introduced at room temperature by means of thescrew 11 into the agglomeration apparatus in such a manner that a longuniform product curtain is formed. The solids mass flow rate is 40 kg/h.It is sprayed with 10 kg/h of steam at an angle a of 20°. The residencetime in the steam zone and thus the contact time with the steam is 1 s.This preferentially forms granules in the size range between 200 and2000 μm. The granules, directly after leaving the steam-treatment zone,have moistures between 2 and 4%. The granules are then dried to residualmoistures below 0.5% in the downstream fluidized bed at bed temperaturesof 30° C. The residence time in the fluidized bed is between 15 and 20min. The agglomerate thus produced is readily flowable, has a good tasteand is outstandingly redispersible. The ratios between the componentsafter the agglomeration correspond to the ratio set in the initialmixture, i.e. no undesirable separation phenomena occur. The agglomeratecan serve as a sachet formulation or else as a tablet formulation. Theagglomerate dissolves in cold water (5 g in 100 ml) in a time of lessthan 15 s into a useable beverage.

We claim:
 1. Process for the agglomeration of a slightly soluble andhydrolytically sensitive substance wherein powder of said slightlysoluble hydrolytically sensitive substance is conducted, together withat least one water-soluble pulverulent binder, in free fall through asteam atmosphere at temperatures between 85° C. and 105° C. essentiallywithout the action of compacting forces, with a residence time in thesteam zone of approximately 0.5 to 10 seconds, and is then initiallydried in further free fall so that, at the points of contact between theprimary particles, only small solid bridges are formed from liquidbridges which are formed owing to the condensation and in which binderis dissolved, and is dried in a subsequent drying operation to a watercontent of less than 5% by weight, in an integrated fluidized bed. 2.Process according to claim 1, wherein the slightly solublehydrolytically sensitive substance used is acetylsalicylic acid powder.3. Process according to claim 1, wherein the residence period in thesteam zone is approximately 1 to 3 seconds.
 4. Process according toclaim 1, wherein, said water-soluble pulverulent binder is selected fromthe group consisting of polyvinylpyrrolidone, polyvinylpyrrolidonederivatives, starch, starch and cellulose derivatives, sugar, sugaralcohols, sugar derivatives, fruit acids or their water-soluble salts,ascorbic acid, amino acids, inorganic salts and mixtures of thesesubstances.
 5. Process according to claim 1, wherein the weight ratio ofthe slightly soluble substances to the water-soluble pulverulent binderis from 1:10 to 10:1.
 6. Process according to claim 1, wherein saidbinders are inorganic salts of the alkali metal and alkaline earth metalseries.
 7. The process of claim 1 wherein said subsequent dryingoperation is to a water content of less than 1% by weight.
 8. Processaccording to claim 4 wherein said sugar derivatives are members of thegroup consisting of maltodextrins and isomaltose.
 9. Process of claim 6,wherein said inorganic salts are selected from the group consisting ofsodium chloride, sodium sulphate, sodium carbonate, sodium hydrogencarbonate and magnesium chloride.